Carbamate esters of hydroxyalkyl piperazino alkyl phenothiazines



United States Patent CARBAMA'IE ESTERS QF HYDRQXYALKYL PIPERAZINO ALKYLPHENOTHIAZINES3.

Margaret H. Sherlock, Bloomfield, and Nathan Sperber,

North .Caldwell, N. J., assignorsltoschering Corporation, Bloomfield, N.J., a corporation of New Jersey N 0 Drawing. Application Novembei' -21,1 956 Serial NoU 623,547 I Claims. (Cl. 260-243) I -X N p /R bngonzom-NN oHneHnmo-IN wherein X represents a halogen atom having am atomicnumber greater than 9 but less than 531, R is a member of the groupconsisting of hydrogen and lower alkyl groups whose combined number ofcarbon atoms is less than 6, and n is a natural number less than--3. Thenew compounds of our invention are extremely potentataraxic agents andare useful in treating or controlling emesis'.

Tliecarbamate esters are approximately 3 to "6 times as,

potent as thefree alcoholin producing'an'ataraxicsor tranquillizingefiect, while the dialkylcarbamate'esters" are 2 to 3 timesas .potent asthe free alcohol. In view of their increased potency, without anysignificant increase in toxicity,a substantial increase in therapeuticratiois achieved.

The piperazine. compounds of. the. general formula wherein R is a loweralkyl group, can be prepared by esterifyingthe free alcohol with adialkylcarbamyl halide such as dimethylcarbamyl chloride. Theesterification is preferably carried out in an inert solvent liketoluene or xylene in the presence of a basic agent such as sodamide orsodium or carried out in pyridine solvent.

The carbamate esters, that is, when R is hydrogen, are prepared bydissolving the phenylcarbonate ester of the free alcohol in liquidammonia whereby the phenoxy group is replaced by -NH Our new piperazinederivatives, in view of their relative insolubility in water, arepreferably transformed into a soluble pharmaceutically acceptable salt.The compounds form salts with a variety of inorganic and strong organicacids such as hydrochloric, maleic, citric, tartaric, phosphoric,sulfuric and related acids.

The following examples are illustrative of methods for preparing ournovel compounds. However, our invention is not to be construed aslimited thereby, the sole limitation being the appended claims.

EXAMPLE A Preparation of the free alcohols l- (Z-HYDROXYETHYI'AA- [3-2-CHLORO-10-PHENOTHI- AZINYL -PROPYLl-PIPERAZINE To a suspension ofsodamide (from 3 g. of sodium) in ice 300ml: of liquid ammonia; there isadded 30 g. of'Q- chlorophenothiazine.' .After stirring for one "hour,19

g. of l-bromo-3-chloropropaneis added The ammonia is allowed toevaporate and to the -residue thereis then added2005ml; of water. Theoilylayer-whichseparates is extracted withether. The etherextractsaredried overanhydrous sodium sulfate, filtered and concentratedr lO- asteam bath. The mixture is decomposedby the addi tion' of 200 ml. ofwater andthe' aqueous mixture' is 'extracted several times-with ether;The ether'layer is thenextracted with dilute hydrochloric acid; The acidlayer' is -basified with sodium hydroxide solution and the resulting oilis extracted-withetherw The ether extracts are' dried, concentrated andthe residuedistilled, yielding the free alcohol of-thisexampleg an oilhaving a BJP. of Its: A dihydrochloride prepared 278'-281- C.'(1.0inm.). in 'ethanolic-hydrogen chloride melts at 225-226 C. afterrecrystallization from ethanol.

By substituting 2-bromophenothiazine in the foregoing reaction there isobtained l-(2-hydroxyethyl) -4-[.3-(2

, bromo-lO-phenothiazinyl)-propylJ-piperazine, B. P. 282

284/l mm., M. F. 97-98? C., M. P. of dihydrochloride 224-225. C. fromethanol.

l (3 hydroxypropyl)-4- [31(2chl0ro-IO-phenothiazinyl)epropyl]-piperazine, M; P. 104-105 C.(from'ethyl acetate) and 1 (3 hydroxypropyl'). 4-[3-(2-bromo-l0 1.

phenothiazinyl )Apropyl] -piperazine are obtained by substituting" 1- 3hydroxypropyl -piperazin'e for 1-(2-hy.-

droxyethyl) -piperazine, in the. following procedures.

EXAMPLE 1 Carbamate of I-(Z-hydroxyethyl) 4- [3; (Z-chldro-JO-phenothiazinyl) -pr0pyl] -piperazine The requisiteinter-mediate, thephenylearbonate ester:

is..--.prepar-ed as wfollowsz Toa. solution of .40 g. of -1-(Z-hydroxyethyl) -4- 3-2-chloro-l O-phenothiazinyl) propylJ-piperazinein 50 ml. of anhydrous pyridine there is added, with cooling, 17.2 g. ofphenyl chlorocarbonate, keeping. thetemperaturebetween 25 and30 C. Afterstirring, at room temperature overnight, 50 ml. of water is added andthe mixture is extracted with chloroform. The chloroform extracts arewashed several times with water, dried over sodium sulfate, andconcentrated in vacuo to a viscous residue consisting of thephenyl'carbonate ester of the before-mentioned alcohol? Asolutionroftfillsg. .ofithe crude-phenylcarbonate, obtained above, inml. of anhydrous ether is added slowly to 500 ml. of liquid ammonia withstirring, in an insulated flask. The reaction mixture is stirred for tenhours after which time all the ammonia has evaporated. To the residuethere is added 200 ml. of water and the mixture is extracted with ether.The ether extracts are washed with dilute sodium carbonate solution andwater; dried over sodium sulfate and concentrated to a residue,consisting of a viscous oil which solidifies upon standing.Recrystallization from benzene-petroleum ether yields the carbamateester of this example, M. P. 8889 C.

The dihydrochloride, which is prepared in absolute ethanol withethanolic hydrogen chloride, melts at 227 228 C., after crystallizationfrom alcohol.

EXAMPLE 2 Dimethyl carbamate 0] ]-(2-hydr0xyethyl)-4- [3-(2-chl0- ro-IO-phenothiazinyl)-pr0pyl] -piperazine A mixture of 40 g. ofl-(2-hydroxyethyl)-4-[3-(1-ch1oro-lO-phenothiazinyl)-propyl]-piperazine, 2.6 g. of pow- Pate'nted Nov. 11, 1958Diethyl carbamate of 1-(3-hydr0xypr0pyl)-4-[(2-chl0-r-10-phen0thiazinyl) -pr0pyl] -piperazz'ne The ester of this example isprepared from the sodium salt (from 1.3 g. of sodium) of 20.5 g. of1-(3-hydroxypropyl) -4- [3-(Z-chloro-10-phenothiazinyl)-propyl]-piperazine and 6.5 g. of diethylcarbamyl chloride according to theprocedure of Example 2.

The free base is converted to its dihydrochloride in' ethan'ol withethanolic hydrogen chloride. The dimaleate is prepared by adding anethyl acetate solution of the ester to an ethyl acetate solution ofmaleic acid. The

salt separates upon cooling the mixture and is removed by filtration.Purification is effected by from ethanol.

' EXAMPLE 4 Carbamate of l- (3-hydroxypropyl) -4- [3-(2-br0m0-10-phenothiazinyl -prqpyl] -piperazine The ester of this example isprepared from 38 g. of 1-(3-hydroxypropyl)-4-[3-(2-bromo10-phenothiazinyl) propyll-piperazine and 17.2 g. of phenylchlorocarbonate, followed by the reaction of the phenylcarbonate withliquid ammonia as in Example 1. The free base is isolatrecrystallizationed as the dihydrochloride with ethanolic hydrogen chlo ride.

EXAMPLE 5 Carbamate of 1-(2-hydr0xyethyl)-4- [3-(2-br0m0-10-phenothiqzinyl -pr0pyl] -piperazine The ester of the example is preparedfrom 22.4 g. of I (2 hydroxyethyl)-4-[3-(2-bromo-l0-phenothiazinyl)-propyll-piperazine and 17.2 g. of phenyl chlorocarbonate followed byammonolysis of the crude phenylcarbonate as in Example 1.

We claim:

1. Pharmaceutically acceptable acid addition salts of bases having theformula;

wherein X is a halogen atom having an atomic number greater than 9 butless than 53, and n is a natural number less than 3.

2. Carbamate of 1-(2-hydroxyethyl)-4-[3-(2-chloro-10-phenothiazinyl)-propyl]-piperazine having the formula:

( lHicmom-N NCH9OH20CNH1 3. Carbamate of1-(3-hydroxypropyl)-4-[3-(2-bromo- 10-phenothiazinyl) -propyl]-piperazine having the formu- Br N O (1H,0H,GH,N N-CHaOHzCHzOO-NH, 4.Carbamate of 1-(2-hydroxyethyl)-4-[3-(2-bromo-10-phenothiazinyl)-propyl]-piperazine having the formula:

HaCHzCHgN N-CHICH1O CNH| 5. Compounds of the group consisting of baseshaving the following formula:

wherein X is a halogen atom having an atomic number greater than 9 butless than 53 and n is a natural number less than 3 and thepharmaceutically acceptable acid addition salts thereof.

References Cited in the file of this patent UNITED STATES PATENTS2,766,235 Cusic Oct. 9, 1956 FOREIGN PATENTS 203,708 Australia Oct. 20,1955

1. PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF BASES HAVING THEFORMULA: